1.What is Trilostane?
Trilostane is a medication used in veterinary medicine to treat Cushing's disease in dogs. Cushing's disease, or hyperadrenocorticism, is a condition characterized by the overproduction of cortisol, a hormone produced by the adrenal glands. Trilostane works by inhibiting the enzyme 3-beta hydroxysteroid dehydrogenase, which is involved in the production of cortisol.
In dogs with Cushing's disease, there is an excessive release of cortisol, leading to various symptoms such as increased thirst and appetite, frequent urination, lethargy, hair loss, and abdominal enlargement. Trilostane helps regulate cortisol levels, managing the signs and symptoms of Cushing's disease.
2.How does Trilostane work?
Trilostane is typically administered orally in the form of capsules or tablets. After oral administration, it is absorbed from the gastrointestinal tract. Taking trilostane with food can optimize its absorption.
Once absorbed, trilostane is distributed throughout the body via the bloodstream. It reaches target tissues, particularly the adrenal glands, where it exerts its inhibitory effects on the enzyme 3-beta hydroxysteroid dehydrogenase.Trilostane undergoes hepatic (liver) metabolism. The liver is responsible for breaking down trilostane into metabolites that may be less active or inactive. The details of trilostane metabolism, including specific metabolites, may vary.
Elimination of trilostane and its metabolites occurs primarily through renal (kidney) excretion. The kidneys filter trilostane and its by-products from the blood, and they are then excreted in the urine.
3.What are the indications for Trilostane?
Trilostane is primarily indicated for the treatment of Cushing's disease (hyperadrenocorticism) in dogs. By blocking this enzyme, trilostane helps regulate and reduce excessive cortisol levels in dogs.
Indications for Trilostane in Dogs:
- Pituitary-Dependent Cushing's: Caused by a tumor on the pituitary gland, leading to increased production of adrenocorticotropic hormone (ACTH), which, in turn, stimulates the adrenal glands to produce excess cortisol.
- Adrenal-Dependent Cushing's: Caused by a tumor on the adrenal glands, resulting in the independent overproduction of cortisol.
- Trilostane is also FDA-approved for the treatment of Alopecia X, a condition characterized by a specific pattern of baldness in certain breeds with thick coats, such as Poodles, Pomeranians, Siberian Huskies, Chow Chows, and Samoyeds.
It's important to note that while Trilostane can effectively manage the symptoms of Cushing's disease, it is not a cure. The goal of treatment is to improve the quality of life for the affected dog by controlling the signs and symptoms associated with excessive cortisol levels.
4.What is the dosage and Administration for Trilostane?
The dosage and administration of Trilostane for dogs with Cushing's disease can vary based on individual patient factors. It's crucial to follow the veterinarian's prescription and guidance for the specific needs of the dog. The following is a general overview, but actual dosages may differ based on the dog's weight, response to treatment, and other considerations:
- Trilostane is typically dosed based on the dog's weight. The usual starting dose may range from 1 to 2 milligrams per kilogram of body weight (1-2 mg/kg). However, individualized dosing is essential, and the veterinarian will calculate the appropriate starting dose for the specific dog.
- Trilostane is administered orally in the form of tablets or capsules.
- It is commonly given once or twice a day. More recent studies have suggested that low-dose twice-daily therapy may be as effective and safer than higher doses given once a day.
- The medication should be given with a meal to optimize absorption.
- Dogs undergoing Trilostane treatment require regular monitoring.
- About 7-14 days after starting Trilostane, an ACTH stimulation test and electrolyte check are typically performed to assess the dog's response to the medication.
- ACTH stimulation tests are usually conducted 3-6 hours post-pill.
- The initial dose is often a starting point, and adjustments may be made based on the dog's clinical response and test results.
- Clinical signs, such as improved energy levels, normal appetite, and reduced drinking and urination, are considered alongside test results.
It's essential for dog owners to strictly adhere to the prescribed dosage and administration schedule. Any concerns or observed side effects should be promptly reported to the veterinarian. Dosage adjustments and further testing may be necessary throughout the course of treatment to ensure the dog's well-being and optimal response to Trilostane therapy.
5.What are the side effects of Trilostane?
Trilostane, like any medication, can have potential side effects. It's important for pet owners to be aware of these and promptly report any concerns to the veterinarian. Common side effects of Trilostane in dogs may include:
- Diarrhea
- Vomiting
- Lack of appetite
- Some dogs may experience lethargy or reduced activity.
- Trilostane inhibits cortisol production, and in some cases, it may lead to reduced adrenal function. Signs of hypoadrenocorticism can include weakness, collapse, and potentially life-threatening complications.
- Trilostane use can result in mild to moderate elevations in serum potassium levels. This is a known effect due to its mechanism of action.
- Trembling or shivering
- Lameness
- Changes in skin or coat
- Although rare, an idiosyncratic reaction called acute adrenal necrosis can occur. This is a severe and potentially life-threatening side effect.
It's important to note that individual dogs may react differently to Trilostane. Additionally, the risk of side effects may be influenced by the dosage, the dog's overall health, and any concurrent medications. Regular monitoring and communication with the veterinarian are crucial during the course of treatment to ensure early detection of any adverse reactions and appropriate adjustments to the treatment plan. If any concerning signs or side effects are observed, it's recommended to seek veterinary advice promptly.
6.What circumstances should Trilostane not be used?
Trilostane is an appropriate treatment option for the specific dog. Here are some circumstances in which Trilostane may not be recommended or should be used with caution:
Trilostane is classified as pregnancy category X by the FDA. It should not be used in pregnant dogs, and caution is advised when handling the medication in households with pregnant individuals.
Trilostane's safety during lactation is not well established, and it may be excreted in milk. Caution should be exercised when using Trilostane in nursing dogs.
Trilostane should be used cautiously in dogs with pre-existing liver or kidney disease. Monitoring of liver and kidney function is typically recommended during treatment.
Dogs with concurrent diabetes mellitus may find diabetic regulation challenging, especially if Trilostane only controls cortisol secretion for part of the day. Careful monitoring and adjustment of diabetes management may be necessary.
Caution is advised when Trilostane is used concurrently with certain medications, such as angiotensin-converting enzyme (ACE) inhibitors or potassium-sparing diuretics. The combination may affect electrolyte balance.
Dogs with a history of hypoadrenocorticism may be at increased risk when using Trilostane. The medication should be used cautiously, and adrenal function should be monitored.
If a dog has a known hypersensitivity or allergy to Trilostane, its use should be avoided.
It's crucial for pet owners to provide a detailed medical history of their dogs to the veterinarian and follow their recommendations closely. Regular veterinary check-ups and monitoring are essential during Trilostane treatment to assess its effectiveness and detect any potential adverse effects.
7.What drug interactions should be noted when using Trilostane?
When using Trilostane, veterinarians should be mindful of potential drug interactions that could affect its efficacy or safety. Here are some notable drug interactions to consider:
- Trilostane should be used with caution in dogs concurrently receiving angiotensin-converting enzyme (ACE) inhibitors. The combination may affect electrolyte balance, especially potassium levels.
- Similar to ACE inhibitors, caution is advised when Trilostane is used alongside potassium-sparing diuretics. This combination may lead to elevated potassium levels.
- Dogs that have recently been treated with mitotane, another medication used in Cushing's disease, should wait at least one month after discontinuing mitotane before starting Trilostane therapy.
It's crucial for veterinarians to be aware of the dog's complete medication history and inform pet owners about potential interactions. Close monitoring of electrolyte levels, especially potassium, may be necessary when Trilostane is administered concurrently with certain medications. Regular veterinary check-ups and communication with the veterinarian are essential to ensure the dog's well-being during treatment.
8.Pharmacology of Trilostane.
Trilostane is a steroidogenesis inhibitor. It is specifically an inhibitor of 3β-hydroxysteroid dehydrogenase (3β-HSD). As a result of this action, trilostane blocks the conversion of Δ5-3β-hydroxysteroids, including pregnenolone, 17α-hydroxypregnenolone, dehydroepiandrosterone (DHEA), and androstenediol, into Δ4-3-ketosteroids, including progesterone, 17α-hydroxyprogesterone, androstenedione, and testosterone, respectively. Consequently, trilostane inhibits the production of all classes of steroid hormones, including androgens, estrogens, progestogens, glucocorticoids, and mineralocorticoids.
The mechanism of action of trilostane in Cushing's syndrome and Conn's syndrome is by inhibiting the production of corticosteroids such as cortisol and aldosterone in the adrenal glands. Trilostane has also been used as an abortifacient due to its inhibition of progesterone synthesis.
Trilostane is not an aromatase inhibitor and hence does not inhibit the conversion of androgens like androstenedione and testosterone into estrogens like estrone and estradiol. However, trilostane may nonetheless inhibit estrogen synthesis by inhibiting androgen synthesis.
In addition to steroidogenesis inhibition, trilostane has been found to act as a noncompetitive antiestrogen, via direct and presumably allosteric interactions with the estrogen receptor. The effectiveness of trilostane in postmenopausal breast cancer may relate to this apparent antiestrogenic activity. Trilostane has also been found to act as an agonist of the androgen receptor. As such, its use in men with prostate cancer may warrant caution.
Trilostane is metabolized in the liver. The major metabolite of trilostane is 17-ketotrilostane. The conversion of trilostane into 17-ketotrilostane is reversible, suggesting that trilostane and 17-ketotrilostane undergo interconversion in the body.[1] 17-Ketotrilostane circulates at 3-fold higher levels than trilostane and is more active than trilostane as a 3β-HSD inhibitor. The elimination half-lives of trilostane and 17-ketotrilostane are both 1.2 hours, with both compounds cleared from the blood within 6 to 8 hours of a dose of trilostane. 17-Ketotrilostane is excreted by the kidneys.